Egesborg, Philippe; Bernard, David N.; Urvoas, Agathe; Gagné, Donald; Mahy, Jean-Pierre; Ricoux, Rémy et Doucet, Nicolas . Selective binding of functionalized porphyrin compounds at the homodimeric interface of human galectin-7 In: 16e Symposium annuel de PROTEO, Mai 2016, Université Laval, Québec.
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Galectins are small soluble lectins that bind beta-galactosides via their carbohydrate recognition domain (CRD). Their ability to dimerize is critical for the crosslinking of glycoprotein receptors and subsequent cellular signaling. This is particularly important for their immunomodulatory role via the induction of T-cell apoptosis. Because galectins play a central role in many pathologies, including cancer, they represent valuable therapeutic targets for drugs or as biomarkers. At present, most inhibitors have been directed towards the CRD, a challenging task in terms of specificity given the high structural homology of the CRD among galectins. However, while the CRD β-galactoside binding site remains highly similar throughout galectin homologues, they display little sequence identity. This observation raises the possibility of targeting various galectins through the use of unusual ligands that would specifically bind galectins in a carbohyrate-independent manner. Here, we report non-carbohydrate ligands, porphyrin compounds functionalized with zinc ions, that specifically bind human galectin-7 (hGal-7). The medical appeal and relevance of porphyrins as photosensitizers in cancer treatment has been amply demonstrated, especially in tumor imaging and photodynamic therapy, potentially providing a means to use these binding affinities and intrinsic physicochemical imaging properties as hGal-7 markers in cancerous tissue progression. We used a combination of fluorescence and NMR titration experiments to specifically define and map the low-micromolar, non-carbohydrate binding sites of porphyrins on the surface of hGal-7. We found that these porphyrin ligands offer limited selectivity with respect to charge and metal, and that their binding affinity to hGal-7(~20µM) is stronger than the previously characterized interactions mediated by glycan-binding residues in the CRD pocket, suggesting that the distinctively high porphyrin affinity to hGal-7 may be biologically significant. To our knowledge, these results highlight the first distinct and structurally characterized non-carbohydrate binding site on the surface of hGal-7, in addition to portraying the only structural characterization of porphyrin binding to human galectins to date.
| Type de document: | Document issu d'une conférence ou d'un atelier |
|---|---|
| Informations complémentaires: | Affiche scientifique |
| Mots-clés libres: | - |
| Centre: | Centre INRS-Institut Armand Frappier |
| Date de dépôt: | 16 août 2018 02:40 |
| Dernière modification: | 16 août 2018 02:40 |
| URI: | https://espace.inrs.ca/id/eprint/5803 |
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